The objective of this research is to study the mechanisms whereby experimental alterations in nerve-muscle cause muscle fiber necrosis. These are continuing studies of our experimental model produced by inhibition of cholinesterase. We will investigate three mechanisms as possible causes for the muscle necrosis; 1) neurogenic mechanisms, effects related to excessive excitatory action due to acetylcholinesterase (AChE) inhibition; 2) myotoxic mechanisms, effects unrelated to AChE inhibition, such as a direct effect on the postsynaptic receptor, endplate membrane and the sarcolemma; and 3) Ca ions overload and energy depletion. We will test the hypothesis that the mechanisms of this necrosis regardless of the primary cause is due to an increase of sarcoplasmic Ca ions associated with a loss of ATP and creatine phosphate. The methods employed are: 1) histochemical, 2) electrophysiological, 3) biochemical, 4) pharmacological, and 5) electron microscopic.